Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis

Kotani, Susumu; Yamauchi, Toshihiko; Teramoto, Takashi; Ogura, Hiroo

doi:10.1016/j.cbi.2008.04.004

Cited by 95 publications

(69 citation statements)

References 33 publications

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“…Donepezil, which is most widely used for the treatment of mild to moderate AD because of modest improvement with minimal side effects among other drugs enhancing central cholinergic functions [39], protects cultured cortical neurons against amyloid-β peptides, N-methyl- D -aspartate/glutamate, and oxygen-glucose deprivation [40,41,42,43]. Furthermore, donepezil enhances adult hippocampal neurogenesis [44]. …”

Section: Discussionmentioning

confidence: 99%

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

et al. 2013

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The cholinergic anti-inflammatory pathway is a neural mechanism that suppresses the innate inflammatory response and controls inflammation employing acetylcholine as the key endogenous mediator. In this study, we investigated the effects of the cholinergic agonists, physostigmine and donepezil, on neurodegeneration, inflammation and oxidative stress during oxygen toxicity in the developing rat brain. The aim of this study was to investigate the level of neurodegeneration, expression of proinflammatory cytokines, glutathione and lipid peroxidation after hyperoxia and treatment with the acetylcholinesterase (AChE) inhibitors, physostigmine and donepezil in the brain of neonatal rats. Six-day-old Wistar rats were exposed to 80% oxygen for 12-24 h and received 100 μg/kg physostigmine or 200 μg/kg donepezil intraperitoneally. Sex-matched littermates kept in room air and injected with normal saline, physostigmine or donepezil served as controls. Treatment with both inhibitors significantly reduced hyperoxia-triggered activity of AChE, neural cell death and the upregulation of the proinflammatory cytokines IL-1β and TNF-α in the immature rat brain on the mRNA and protein level. In parallel, hyperoxia-induced oxidative stress was reduced by concomitant physostigmine and donepezil administration, as shown by an increased reduced/oxidized glutathione ratio and attenuated malondialdehyde levels, as a sign of lipid peroxidation. Our results suggest that a single treatment with AChE inhibitors at the beginning of hyperoxia attenuated the detrimental effects of oxygen toxicity in the developing brain and may pave the way for AChE inhibitors, which are currently used for the treatment of Alzheimer's disease, as potential candidates for adjunctive neuroprotective therapies to the immature brain.

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Section: Discussionmentioning

confidence: 99%

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

et al. 2013

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“…Thus, the extant literature would suggest that the observed hippocampal alterations in cocaine-addicted subjects could be a result of chronic cocaine use and that disruptions in dorsal hippocampal cholinergic regulation could alter the ability of cocaine-addicted subjects to extinguish cocainecued learning. Enhancement of hippocampus neurogenesis by a cholinergic agonist (Kotani et al, 2008), a process inhibited by chronic cocaine administration (Noonan et al, 2008;Yamaguchi et al, 2004), also points to putative function of the cholinergic system in cocaine-induced hippocampal functioning.…”

Section: Regions Of Interestmentioning

confidence: 93%

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Adinoff

Devous

Williams

et al. 2010

Neuropsychopharmacol

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Changes in the brain's cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. An emerging preclinical literature also reveals that acetylcoholine may have an important function in addictive processes, including reward, learning, and memory. This study was designed to assess alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. On three separate days, 23 1-to 6-week abstinent, cocaine-(and mostly nicotine-) addicted subjects and 22 sex-, age-, and race-matched control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (po0.005) in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. Cocaine addicted and controls differ in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory. Cholinergic systems may offer a pharmacologic target for cocaine addiction treatment.

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“…In vivo animal studies revealed that the ChEIs tacrine and galantamine enhance neurogenesis in the forebrain subventricular zone and hippocampal dentate gyrus. Similarly, Kotani et al [33,34] reported that donepezil enhances adult rat hippocampal neurogenesis and is antagonized by scopolamine, a muscarinic ACh receptor antagonist. Leyhe et al [28] reported that high-dose (10 mg/day) donepezil ameliorated serum BDNF by a 15-month treatment of patients with mild cognitive impairment (MCI) to mild AD.…”

Section: Cholinergic Activity and Bdnfmentioning

confidence: 97%

Beyond the Hypothesis of Serum Anticholinergic Activity in Alzheimer's Disease: Acetylcholine Neuronal Activity Modulates Brain-Derived Neurotrophic Factor Production and Inflammation in the Brain

Hachisu

Konishi²,

Hosoi

et al. 2015

Neurodegener Dis

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The brain of Alzheimer's disease (AD) patients is characterized by neurodegeneration, especially an acetylcholine (ACh) neuronal deficit with accumulation of β-amyloid protein, which leads to oxygen stress and inflammation. The active oxygen directly damages the neuron by increasing intracellular Ca²⁺. The inflammation is due to activation of the microglia, thereby producing cytokines which inhibit the production of brain-derived neurotrophic factor (BDNF). As the BDNF acts by neuronal protection, synaptogenesis and neurogenesis, the reduction of BDNF in the brain of AD patients worsens the symptoms of AD. On the other hand, treatment of AD patients with a cholinesterase inhibitor enhances ACh activity and inhibits inflammation. Then the expression of BDNF is restored and neuroprotection reestablished. However, there are several reports which showed controversial results concerning the relationship between BDNF and AD. We speculate that BDNF is related to some neurocognitive process and reflects neuronal activity in other neurodegenerative and neuropsychiatric disorders and that in the mild cognitive impairment stage, BDNF and choline acetyltransferase (ChAT) activities are hyperactivated because of a compensatory mechanism of AD pathology. In contrast, in the mild stage of AD, BDNF and ChAT activity are downregulated.

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Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis

Cited by 95 publications

References 33 publications

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Beyond the Hypothesis of Serum Anticholinergic Activity in Alzheimer's Disease: Acetylcholine Neuronal Activity Modulates Brain-Derived Neurotrophic Factor Production and Inflammation in the Brain

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